The development of obesity and non-alcoholic fatty liver disease (NAFLD) are closely linked, yet the molecular mechanisms underlying these pathologies are poorly understood. Currently, no treatment exists for individuals diagnosed with NAFLD. We have identified Tox (thymocyte selection-associated high mobility group box) as a hepatic transcription factor that is strongly induced during NAFLD. We have also identified that the whole-body deletion of Tox in mice prevents the development of NAFLD, suggesting that Tox plays a crucial role in mediating central metabolism. However, the metabolic effects of Tox specifically in hepatic metabolism and the consequent effects on the development of NAFLD have not been reported. We therefore hypothesize that the inhibition of hepatic Tox expression will prevent NAFLD thus offering a novel target in the treatment of NAFLD. This proposal employs novel mouse genetic models and state of the art NMR techniques to address the link between Tox, hepatic metabolism and NAFLD.